Food Allergen Risk Assessment Approaches

Risk Assessment for FoodRisk Assessment for Food
AllergensAllergens

Food Allergy Research
and Resource Program
 2005
Risk Assessment Approaches toRisk Assessment Approaches to
Evaluation ofEvaluation of
Food Allergen HazardsFood Allergen Hazards
Hazard IdentificationHazard Identification
Dose/Response EvaluationDose/Response Evaluation
Exposure AssessmentExposure Assessment
Risk CharacterizationRisk Characterization

 2005
Dose/Response EvaluationDose/Response Evaluation
Trace amounts can elicit allergicTrace amounts can elicit allergic
reactionsreactions
Severity of response is related directly toSeverity of response is related directly to
dosedose
Individuals vary in degree of sensitivityIndividuals vary in degree of sensitivity
How much is too much?How much is too much?

 2005
Exposure AssessmentExposure Assessment
How frequently are food productsHow frequently are food products
contaminated with potentially hazardouscontaminated with potentially hazardous
levels of unlabeled allergens?levels of unlabeled allergens?
How frequently do allergic reactions occur?How frequently do allergic reactions occur?

 2005

 2005
Sources of CluesSources of Clues
Regarding Food Allergen ThresholdsRegarding Food Allergen Thresholds
Allergen cross contact episodesAllergen cross contact episodes
Double-blind, placebo-controlled foodDouble-blind, placebo-controlled food
challengeschallenges
Immunotherapy trialsImmunotherapy trials
Clinical threshold experimentsClinical threshold experiments

 2005
INTERPRETATION PROBLEMSINTERPRETATION PROBLEMS
ALLERGEN CROSS CONTACT EPISODESALLERGEN CROSS CONTACT EPISODES
Past analytical methods may not have yieldedPast analytical methods may not have yielded
accurate resultsaccurate results
Lack of accurate information on amount ofLack of accurate information on amount of
allergenic food residuesallergenic food residues
Uncertainty about amount of food eatenUncertainty about amount of food eaten
Questions about other sources of allergenQuestions about other sources of allergen
Individual variability in thresholdIndividual variability in threshold

11stst
Threshold ConferenceThreshold Conference
September, 1999September, 1999
Hilton Head, South Carolina, USAHilton Head, South Carolina, USA

 2005
11stst
Results:Results:
Taylor et al. 2002. Factors affecting theTaylor et al. 2002. Factors affecting the
determination of threshold doses fordetermination of threshold doses for
allergenic foods: how much is too much?allergenic foods: how much is too much?
J. Allergy Clin. Immunol. 109: 24-30.J. Allergy Clin. Immunol. 109: 24-30.

 2005
11stst
Results:Results:
– Considerable data presented on low doseConsiderable data presented on low dose
challenges for peanut, egg and cows’ milkchallenges for peanut, egg and cows’ milk
– More limited data available on low doseMore limited data available on low dose
challenges to other allergenic foods: fish,challenges to other allergenic foods: fish,
mustard, soybean and tree nutsmustard, soybean and tree nuts

 2005
11stst
FoodFood
ProtocolProtocol
LowestLowest
Provoking DosesProvoking Doses
(mg protein)(mg protein)
No. PatientsNo. Patients
PeanutPeanut 0.25 mg (0.25 – 66 mg)0.25 mg (0.25 – 66 mg) 306306
EggEgg 0.13 mg (0.13 – 200 mg)0.13 mg (0.13 – 200 mg) 281281
Cows’ MilkCows’ Milk 0.6 mg (0.6 – 180 mg)0.6 mg (0.6 – 180 mg) 299299

 2005
11stst
Major ConclusionsMajor Conclusions
Threshold doses do exist for commonly allergenicThreshold doses do exist for commonly allergenic
foodsfoods
Thresholds were finite, measurable, and above zeroThresholds were finite, measurable, and above zero
Premature to reach consensus on threshold dosesPremature to reach consensus on threshold doses
for specific foodsfor specific foods

 2005
11stst
Secondary Observations/ OpinionsSecondary Observations/ Opinions
Reactions occur to hidden/ undeclared allergens inReactions occur to hidden/ undeclared allergens in
foodsfoods
The severity of reactions to undeclared allergensThe severity of reactions to undeclared allergens
increases with the dose of exposureincreases with the dose of exposure
Low/ very low dose exposures (LOAELs) result inLow/ very low dose exposures (LOAELs) result in
mild, reversible symptomsmild, reversible symptoms

22ndnd
FARRP ThresholdFARRP Threshold
ConferenceConference
May 20-21, 2002May 20-21, 2002
Palm Beach, FLPalm Beach, FL

 2005
22ndnd
ResultsResults::
– Taylor et al. 2004. A consensus protocol for theTaylor et al. 2004. A consensus protocol for the
determination of the threshold doses fordetermination of the threshold doses for
allergenic foods: how much is too much? Clin.allergenic foods: how much is too much? Clin.
Exp. Allergy 34: 689-695.Exp. Allergy 34: 689-695.

33rdrd
FARRP Threshold ConferenceFARRP Threshold Conference
October 4-5, 2004October 4-5, 2004
Camp De Mar, Mallorca, SpainCamp De Mar, Mallorca, Spain

 2005
Why model dose-response?Why model dose-response?
It may not be feasible to design studies with sufficient power to giveIt may not be feasible to design studies with sufficient power to give
the desired degree of safety assurancethe desired degree of safety assurance (e.g., 268 patients(e.g., 268 patients and no reactionsand no reactions areare
required to say with 95% confidence that the reaction rate is less than 1%).required to say with 95% confidence that the reaction rate is less than 1%).
A conventional approach, applying a safety factor to a no effect levelA conventional approach, applying a safety factor to a no effect level
cannot easily be applied:cannot easily be applied:
▪ many challenge studies do not yield a no-effect levelmany challenge studies do not yield a no-effect level
▪ some challenge studies exclude individuals who have suffered a severesome challenge studies exclude individuals who have suffered a severe
response, (are severe reactors the most sensitive?)response, (are severe reactors the most sensitive?)
▪ No agreement yet on uncertainty factorsNo agreement yet on uncertainty factors
Modelling is an accepted way of defining the probability of rare eventsModelling is an accepted way of defining the probability of rare events
with potentially severe consequenceswith potentially severe consequences

Proportion of
reactions
Dose
100%
50%
10%
Log-Linear
model
Lower 95%
confidence
interval
‘Threshold’
Figure 4: Diagram showing one possible definition for a
allergen threshold using a log-linear model.

 2005
Classical Risk AssessmentClassical Risk Assessment
Typical Uncertainty Factors:Typical Uncertainty Factors:
10x – Extrapolation from animals to humans10x – Extrapolation from animals to humans
10x – Inter-individual variation10x – Inter-individual variation
TDI = NOAEL ÷ 100 (in rats)TDI = NOAEL ÷ 100 (in rats)

 2005
Risk Assessment for FoodRisk Assessment for Food
AllergensAllergens
Determine the NOAEL for specific allergenicDetermine the NOAEL for specific allergenic
food among humans with allergy to that foodfood among humans with allergy to that food
Apply uncertainty factor to obtain TDIApply uncertainty factor to obtain TDI

 2005
Determination of NOAELDetermination of NOAEL
Challenge large number of allergic individualsChallenge large number of allergic individuals
Identify NOAEL for each patientIdentify NOAEL for each patient
Identify LOAEL for each patientIdentify LOAEL for each patient
Determine variation between individuals inDetermine variation between individuals in
NOAELsNOAELs
Standardized protocol leads to consistentStandardized protocol leads to consistent
interpretation of resultsinterpretation of results

 2005
Uncertainty FactorsUncertainty Factors
No animal to human extrapolation neededNo animal to human extrapolation needed
Have already selected sensitive subset ofHave already selected sensitive subset of
human populationhuman population
Did we include the most sensitive individual?Did we include the most sensitive individual?
Infants vs. adultsInfants vs. adults

 2005
Relevant LiteratureRelevant Literature
Published LOAELsPublished LOAELsPeanut
May (1976) 3
Bock et al. (1978) 14
Atkins et al. (1985) 2
Pastorello et al. (1988) 2
Oppenheimer et al. (1992) 11
Moneret-Vautrin et al. (1995) 2
Hourihane et al. (1997) 14
Sicherer et al. (2000) 24
Wensing et al. (2002) 26
Taylor et al. (2002) 306*
Morisset et al. (2003) 103
Grimshaw et al. (2003) 4
Leung et al. (2003) 84

 2005
Published LOAELsPublished LOAELs
Egg
May (1976) 4
Bock et al. (1978) 10
Atkins et al. (1985) 1
Norgaard & Bindslev-Jensen (1992) 7
Caffarelli et al. (1995) 13
Eggesbo et al. (2001) 9
Osterballe & Bindslev-Jensen (2003) 56

 2005
Published LOAELsPublished LOAELs
Milk
May (1976) 1
Bock et al. (1978) 10
Bernstein et al. (1982) 5
Hill et al. (1988) 68
Baehler et al. (1995) 10
Norgaard & Bindslev-Jensen (1992) 4
Meglio et al. (2004) 13

 2005
Uncertainties RegardingUncertainties Regarding
Establishment of Threshold DosesEstablishment of Threshold Doses
Adults vs. children (mg vs. mg/kg)Adults vs. children (mg vs. mg/kg)
Nature of challenge materialNature of challenge material
Allergen content of challenge materialAllergen content of challenge material

 2005
Nature of Challenge MaterialNature of Challenge Material
PeanutPeanut EggEgg MilkMilk
Ground peanutGround peanut Egg whiteEgg white Whole milkWhole milk
Peanut flourPeanut flour Dried egg whiteDried egg white Non-fat dry milkNon-fat dry milk
Peanut butterPeanut butter Whole eggWhole egg Infant formulaInfant formula
Dried whole eggDried whole egg
Raw vs. cookedRaw vs. cooked

 2005
Uncertainties About ChallengeUncertainties About Challenge
MaterialsMaterials
Studies should be compared by using proteinStudies should be compared by using protein
contentcontent
If the protein content of the challenge material wasIf the protein content of the challenge material was
not determined experimentally or cannot benot determined experimentally or cannot be
determined with reliable factors, then the studydetermined with reliable factors, then the study
should be rejected from consideration inshould be rejected from consideration in
establishment of thresholdsestablishment of thresholds
Well-characterized challenge material: NFDM,Well-characterized challenge material: NFDM,
dried egg white, soy flourdried egg white, soy flour
Thresholds should be established in terms that canThresholds should be established in terms that can
be related to analytical methods (mg food)be related to analytical methods (mg food)

 2005
Blinding of challenges (single-blind vs.Blinding of challenges (single-blind vs.
double-blind)double-blind)
Oral vs. labial challengesOral vs. labial challenges
Choice of dosages for challengesChoice of dosages for challenges

 2005
LOAELs vs. NOAELsLOAELs vs. NOAELs
Uncertainty in using LOAEL to establishUncertainty in using LOAEL to establish
threshold dosethreshold dose
Patient selection and exclusion of severelyPatient selection and exclusion of severely
affected patientsaffected patients
Variability in individual threshold dosesVariability in individual threshold doses

 2005
NOAELs vs. LOAELsNOAELs vs. LOAELs
Diagnostic challenges report only LOAELsDiagnostic challenges report only LOAELs
NOAELs may not be recordedNOAELs may not be recorded
In many cases (how many?), the patient hasIn many cases (how many?), the patient has
responded to the lowest dose administeredresponded to the lowest dose administered
How far above the NOAEL is the LOAEL?How far above the NOAEL is the LOAEL?
If using LOAEL, how big should the UF be?If using LOAEL, how big should the UF be?

 2005
NOAELs vs. LOAELsNOAELs vs. LOAELs
Size of UFSize of UF
UF = 1 if LOAEL based upon subjective symptomsUF = 1 if LOAEL based upon subjective symptoms
UF = 2 if LOAEL based on mild, objectiveUF = 2 if LOAEL based on mild, objective
symptoms at first dosesymptoms at first dose andand very low doses (0.1 –very low doses (0.1 –
20 mg) were given20 mg) were given
UF = ? If LOAEL based on objective symptoms, atUF = ? If LOAEL based on objective symptoms, at
first dose and higher doses (400+ mg) were givenfirst dose and higher doses (400+ mg) were given
Use NOAEL in cases where objective symptomsUse NOAEL in cases where objective symptoms
occurred at doses above the initial doseoccurred at doses above the initial dose

 2005
Selection of SubjectsSelection of Subjects
Diagnostic evaluations (DBPCFC) may beDiagnostic evaluations (DBPCFC) may be
representative of the whole population ofrepresentative of the whole population of
allergic individualsallergic individuals
– Referral clinics?Referral clinics?
Clinical threshold studies may be skewedClinical threshold studies may be skewed
toward the more highly sensitivetoward the more highly sensitive

 2005
Selection of SubjectsSelection of Subjects
Sicherer et al. 2000. Dose-response in double-Sicherer et al. 2000. Dose-response in double-
blind, placebo-controlled oral food challenge inblind, placebo-controlled oral food challenge in
children with atopic dermatitis. J. Allergy Clin.children with atopic dermatitis. J. Allergy Clin.
Immunol. 105: 582-586.Immunol. 105: 582-586.
DBPCFC of 53 soy-allergic childrenDBPCFC of 53 soy-allergic children
– 28% reacted at first dose (400 or 500 mg)28% reacted at first dose (400 or 500 mg)
– 53% reacted at intermediate doses53% reacted at intermediate doses
– 19% reacted at final dose (2.0 or 2.5 g) or on open19% reacted at final dose (2.0 or 2.5 g) or on open
challengechallenge
Soy protein or soy flour?Soy protein or soy flour?

 2005
Minimal Eliciting Dose Peanut (n=103)Minimal Eliciting Dose Peanut (n=103)
Patients with suggestive symptoms (OAS – shock)Patients with suggestive symptoms (OAS – shock)
SBPCFC or DBPCFC, 5 active dosesSBPCFC or DBPCFC, 5 active doses
20 min interval20 min interval
Dose range: 5 – 700mg/10 – 5000mgDose range: 5 – 700mg/10 – 5000mg
Roasted crushed peanuts in mashed potatoesRoasted crushed peanuts in mashed potatoes
Severe symptoms: abdominal pain (3.3%), asthmaSevere symptoms: abdominal pain (3.3%), asthma
(20%), drop in BP (3%)(20%), drop in BP (3%)
AgeAge EDED (cum)(cum)
ChildrenChildren < 15 mg - > 7110 mg< 15 mg - > 7110 mg
AdultsAdults < 15 mg - > 7110 mg< 15 mg - > 7110 mg
(one patient(one patient 5 mg)5 mg)
Morisset et al. CEA 2003;33:1046-51.

 2005
Severely Affected IndividualsSeverely Affected Individuals
Have they been excluded from challenge trials?Have they been excluded from challenge trials?
Do they have lower minimal eliciting doses?Do they have lower minimal eliciting doses?
Do they experience severe reactions at very lowDo they experience severe reactions at very low
doses?doses?
Have they simply made big mistakes in theirHave they simply made big mistakes in their
avoidance diets?avoidance diets?

 2005
Minimal Eliciting Dose PMinimal Eliciting Dose Peanuteanut (n=26(n=26))
Adult patients with suggestive history (OAS – shock)Adult patients with suggestive history (OAS – shock)
Double blind challenge, 7 active doses, 7 placeboDouble blind challenge, 7 active doses, 7 placebo
Randomly interspersed, 15 – 30 min intervalRandomly interspersed, 15 – 30 min interval
85% defatted roasted peanut flour in mashed potatoes85% defatted roasted peanut flour in mashed potatoes
26/26 had symptoms, 5/26 objective26/26 had symptoms, 5/26 objective
Symptoms: OAS (26), lipswelling (3), nausea (2), vomitingSymptoms: OAS (26), lipswelling (3), nausea (2), vomiting
(2)(2)
Clinical score: mild, moderate, severeClinical score: mild, moderate, severe
AgeAge (mean)(mean) ED obj (ED obj (μμg)g) ED objED obj (cum)(cum) ((μμg)g)
2525 10 - 30 14.43 – 4410 - 30 14.43 – 44
Wensing et al. JACI 2002;110:915-20.

Food Allergen Risk Assessment Approaches

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